title: HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q.
abstract: The hereditary deficiency of 3-hydroxy-3-methylglutaryl (HMG) CoA lyase (HL; OMIM 246450 [http://www3.ncbi.nlm.nih. gov:80/htbin-post/Omim/dispmim?246450]) results in episodes of hypoketotic hypoglycemia and coma and is reported to be frequent and clinically severe in Saudi Arabia. We found genetic diversity among nine Saudi HL-deficient probands: six were homozygous for the missense mutation R41Q, and two were homozygous for the frameshift mutation F305fs(-2). In 32 non-Saudi HL-deficient probands, we found three R41Q alleles and also discovered four other deleterious point mutations in codons 41 and 42: R41X, D42E, D42G, and D42H. In purified mutant recombinant HL, all four missense mutations in codons 41 and 42 cause a marked decrease in HL activity. We developed a screening procedure for HL missense mutations that yields residual activity at levels comparable to those obtained using purified HL peptides. Codons 41 and 42 are important for normal HL catalysis and account for a disproportionate 21 (26%) of 82 of mutant alleles in our group of HL-deficient probands.
authors.affiliation: Service de genetique medicale, Hopital Sainte-Justine, Montreal, Quebec H3T 1C5, Canada. mitchell@ere.umontreal.ca
authors.forename: G A
authors.initials: GA
authors.lastname: Mitchell
authors.forename: P T
authors.initials: PT
authors.lastname: Ozand
authors.forename: M F
authors.initials: MF
authors.lastname: Robert
authors.forename: L
authors.initials: L
authors.lastname: Ashmarina
authors.forename: J
authors.initials: J
authors.lastname: Roberts
authors.forename: K M
authors.initials: KM
authors.lastname: Gibson
authors.forename: R J
authors.initials: RJ
authors.lastname: Wanders
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: I
authors.initials: I
authors.lastname: Chevalier
authors.forename: E
authors.initials: E
authors.lastname: Plöchl
authors.forename: H
authors.initials: H
authors.lastname: Miziorko
mesh_terms: D001483:Base Sequence; D003001:Cloning, Molecular; D003062:Codon; D003128:Coma / Q000235:genetics; D017931:DNA Primers; D005006:Ethnicity; D005091:Exons; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics; D007438:Introns; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D007652:Oxo-Acid-Lyases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D012529:Saudi Arabia / Q000453:epidemiology; D013577:Syndrome
chemical_list: D003062:Codon; D017931:DNA Primers; D011994:Recombinant Proteins; D007652:Oxo-Acid-Lyases; C021410:3-hydroxy-3-methylglutaryl-coenzyme A lyase